Functional characterization of two M42 aminopeptidases erroneously annotated as cellulases

Several aminopeptidases of the M42 family have been described as tetrahedral-shaped dodecameric (TET) aminopeptidases. A current hypothesis suggests that these enzymes are involved, along with the tricorn peptidase, in degrading peptides produced by the proteasome. Yet the M42 family remains ill defined, as some members have been annotated as cellulases because of their homology with CelM, formerly described as an endoglucanase of Clostridium thermocellum. Here we describe the catalytic functions and substrate profiles CelM and of TmPep1050, the latter having been annotated as an endoglucanase of Thermotoga maritima. Both enzymes were shown to catalyze hydrolysis of nonpolar aliphatic L-amino acid-pNA substrates, the L-leucine derivative appearing as the best substrate. No significant endoglucanase activity was measured, either for TmPep1050 or CelM. Addition of cobalt ions enhanced the activity of both enzymes significantly, while both the chelating agent EDTA and bestatin, a specific inhibitor of metalloaminopeptidases, proved inhibitory. Our results strongly suggest that one should avoid annotating members of the M42 aminopeptidase family as cellulases. In an updated assessment of the distribution of M42 aminopeptidases, we found TET aminopeptidases to be distributed widely amongst archaea and bacteria. We additionally observed that several phyla lack both TET and tricorn. This suggests that other complexes may act downstream from the proteasome

MRI in multiple myeloma : a pictorial review of diagnostic and post-treatment findings

Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity. This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message aEuro cent Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. aEuro cent Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. aEuro cent Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. aEuro cent Combined morphological and functional MRI provides optimal bone marrow assessment for staging. aEuro cent Combined morphological and functional MRI is of considerable value in treatment follow-up

Learned Monocular Depth Priors in Visual-Inertial Initialization

Visual-inertial odometry (VIO) is the pose estimation backbone for most AR/VR and autonomous robotic systems today, in both academia and industry. However, these systems are highly sensitive to the initialization of key parameters such as sensor biases, gravity direction, and metric scale. In practical scenarios where high-parallax or variable acceleration assumptions are rarely met (e.g. hovering aerial robot, smartphone AR user not gesticulating with phone), classical visual-inertial initialization formulations often become ill-conditioned and/or fail to meaningfully converge. In this paper we target visual-inertial initialization specifically for these low-excitation scenarios critical to in-the-wild usage. We propose to circumvent the limitations of classical visual-inertial structure-from-motion (SfM) initialization by incorporating a new learning-based measurement as a higher-level input. We leverage learned monocular depth images (mono-depth) to constrain the relative depth of features, and upgrade the mono-depth to metric scale by jointly optimizing for its scale and shift. Our experiments show a significant improvement in problem conditioning compared to a classical formulation for visual-inertial initialization, and demonstrate significant accuracy and robustness improvements relative to the state-of-the-art on public benchmarks, particularly under motion-restricted scenarios. We further extend this improvement to implementation within an existing odometry system to illustrate the impact of our improved initialization method on resulting tracking trajectories

Patients' satisfaction with community treatment: a pilot cross-sectional survey adopting multiple perspectives.

ACCESSIBLE SUMMARY: Patients' satisfaction is scarcely studied within the context of community treatment for adolescents. Thus, this study adopts a multiple perspective on patients' satisfaction (including service users as well as staff members). The results highlighted that all informants (patients, foster carers in foster homes and professional caregivers from community treatment teams) perceived the patients to be satisfied, with foster carers reporting the highest patient satisfaction rate. Considering the patient satisfaction rate from multiple perspectives provides complementary understandings. Clinical outcomes and, specifically, a reduction in emotional difficulties were related to patient's satisfaction, but only from the patients' perspective. ABSTRACT: Community treatment (CT) teams in Switzerland provide care to patients who are unable to use regular child and adolescent mental health services (i.e. inpatient and outpatients facilities). No study has considered patients' self-rated satisfaction alongside with staff members' perspectives on patient satisfaction. Thus, adopting a cross-sectional survey design, we collected patients' satisfaction using the Client Satisfaction Questionnaire (CSQ-8), rated by multiple informants (patients, foster carers in foster homes and professional caregivers from CT teams). Professional caregivers assessed clinical outcomes using the Health of the Nation Outcome Scale for Children and Adolescents. The results indicated that all informants were satisfied with the community treatment teams. The satisfaction scores were not correlated across informants; however, the alleviation of emotional symptoms was correlated with patients' satisfaction. This study indicated that the use of a combined approach including the views of service users and professionals gives important complementary information. Finally, in our sample, lower emotional symptoms were linked to enhanced patient satisfaction. This study demonstrated the importance of considering multiple perspectives to obtain the most accurate picture of patients' satisfaction. Second, focusing on the reduction of emotional symptoms might lead to a higher degree of patients' satisfaction

Development and Optimization of a GMP-Compliant Manufacturing Process for a Personalized Tumor Lysate Dendritic Cell Vaccine.

With the emergence of immune checkpoint inhibitors and adoptive T-cell therapies, there is a considerable interest in using personalized autologous dendritic cell (DC) vaccines in combination with T cell-targeting immunotherapies to potentially maximize the therapeutic impact of DC vaccines. Here, we describe the development and optimization of a Good Manufacturing Practice (GMP)-compliant manufacturing process based on tumor lysate as a tumor antigen source for the production of an oxidized tumor cell lysate loaded DC (OC-DC) vaccine. The manufacturing process required one day for lysate preparation and six days for OC-DC vaccine production. Tumor lysate production was standardized based on an optimal tumor digestion protocol and the immunogenicity was improved through oxidation using hypochloric acid prior to freeze-thaw cycles resulting in the oxidized tumor cell lysate (OC-L). Next, monocytes were selected using the CliniMACS prodigy closed system and were placed in culture in cell factories in the presence of IL-4 and GM-CSF. Immature DCs were loaded with OC-L and matured using MPLA-IFNγ. After assessing the functionality of the OC-DC cells (IL12p70 secretion and COSTIM assay), the OC-DC vaccine was cryopreserved in multiple doses for single use. Finally, the stability of the formulated doses was tested and validated. We believe this GMP-compliant DC vaccine manufacturing process will facilitate access of patients to personalized DC vaccines, and allow for multi-center clinical trials

From spinal central pattern generators to cortical network: integrated BCI for walking rehabilitation

Success in locomotor rehabilitation programs can be improved with the use of brain-computer interfaces (BCIs). Although a wealth of research has demonstrated that locomotion is largely controlled by spinal mechanisms, the brain is of utmost importance in monitoring locomotor patterns and therefore contains information regarding central pattern generation functioning. In addition, there is also a tight coordination between the upper and lower limbs, which can also be useful in controlling locomotion. The current paper critically investigates different approaches that are applicable to this field: the use of electroencephalogram (EEG), upper limb electromyogram (EMG), or a hybrid of the two neurophysiological signals to control assistive exoskeletons used in locomotion based on programmable central pattern generators (PCPGs) or dynamic recurrent neural networks (DRNNs). Plantar surface tactile stimulation devices combined with virtual reality may provide the sensation of walking while in a supine position for use of training brain signals generated during locomotion. These methods may exploit mechanisms of brain plasticity and assist in the neurorehabilitation of gait in a variety of clinical conditions, including stroke, spinal trauma, multiple sclerosis, and cerebral palsy

Quantifying the Effects of Prosody Modulation on User Engagement and Satisfaction in Conversational Systems

As voice-based assistants such as Alexa, Siri, and Google Assistant become ubiquitous, users increasingly expect to maintain natural and informative conversations with such systems. However, for an open-domain conversational system to be coherent and engaging, it must be able to maintain the user's interest for extended periods, without sounding boring or annoying. In this paper, we investigate one natural approach to this problem, of modulating response prosody, i.e., changing the pitch and cadence of the response to indicate delight, sadness or other common emotions, as well as using pre-recorded interjections. Intuitively, this approach should improve the naturalness of the conversation, but attempts to quantify the effects of prosodic modulation on user satisfaction and engagement remain challenging. To accomplish this, we report results obtained from a large-scale empirical study that measures the effects of prosodic modulation on user behavior and engagement across multiple conversation domains, both immediately after each turn, and at the overall conversation level. Our results indicate that the prosody modulation significantly increases both immediate and overall user satisfaction. However, since the effects vary across different domains, we verify that prosody modulations do not substitute for coherent, informative content of the responses. Together, our results provide useful tools and insights for improving the naturalness of responses in conversational systems.Comment: Published in CHIIR 2020, 4 page